STAT6 protein may have role in PH tied to sleep apnea, study finds
Protein's levels high in lungs of mice with disease induced by oxygen deprivation
Activation of an immune signaling molecule called STAT6 may lead to pulmonary hypertension (PH) in people with oxygen deprivation due to obstructive sleep apnea, according to a recent study in mice.
Obstructive sleep apnea is a common sleep disorder characterized by chronic intermittent hypoxia, or repeated episodes of stopping and starting to breathe while asleep.
In the study, STAT6 levels were elevated in the lungs of a mouse model of intermittent hypoxia-induced PH. Deleting the protein eased disease severity in the mice and reduced signaling of an immune pathway called the Th2 response that’s seen to be a driver of PH.
“These findings exhibit the critical role of STAT6 in the pathogenesis [development] of CIH [chronic intermittent hypoxia] induced PH by regulating Th2 immune response,” the researchers wrote. “STAT6 could be a significant therapeutic target for [obstructive sleep apnea-related] PH,” they added.
Obstructive sleep apnea is known to raise the risk of pulmonary hypertension
The study, “STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines,” was published in Respiratory Research.
Breathing starts and stops repeatedly during sleep with obstructive sleep apnea due to a blockage or narrowing in the airways, leading to chronic intermittent hypoxia.
The sleep disorder raises a risk of PH, elevated pressure in the blood vessels of the lungs (the pulmonary arteries), and other cardiovascular problems.
Factors underlying how PH arises in people with this disorder are not completely understood, but inflammation is believed to play a role. Research has shown that low oxygen conditions create an inflammatory environment capable of driving vascular remodeling, a series of structural changes in the pulmonary arteries that contribute to PH, the study noted.
One possible key player is STAT6, a protein involved in lung inflammatory responses. STAT6 is involved in the activation of the Th2 immune response, which is implicated in PH development and progression. It also has been found to be elevated in people with obstructive sleep apnea and animal models of chronic intermittent hypoxia.
Scientists in China explored the potential role of STAT6 and Th2 responses in driving intermittent hypoxia-induced PH.
PH, vascular remodeling less severe in mice lacking STAT6 protein
They found phosphorylated STAT6 — an activated form of the protein — at higher levels in lung tissue of a mouse model of hypoxia-induced PH relative to tissue from the lungs of healthy mice, along with signs of an increased Th2 immune response.
When the mice were genetically engineered to lack STAT6, PH severity and signs of vascular remodeling fell. The Th2 immune response was suppressed, including reductions in Th2 immune cell populations and related signaling molecules, namely IL-13 and IL-4.
Further experiments in cultured pulmonary artery cells showed the excessive cell growth characteristic of vascular remodeling in PH appeared to be driven by IL-4; specifically, the signaling molecule showed an ability to activate STAT6.
“In summary, our study demonstrates that IL-4/STAT6 participates in CIH-induced PH by regulating Th2 immune responses,” the researchers wrote, noting that its findings help to position STAT6 as a therapeutic target for PH associated with chronic intermittent hypoxia.
They noted, however, that a number of molecules other than IL-4 can lead to STAT6 activation and may play a role in the process.
“Further validation of these factors’ effects on STAT6 in the CIH model is required,” the researchers wrote.
Future studies aiming to confirm STAT6’s role in sleep apnea-induced PH would need to look at the protein’s levels in lung tissue from patients, as animal models do not fully replicate the features of human disease, they added.
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